DHHS / FDA / CDRH 1 FDA Summary CryoLife BioGlue P Lead FDA Reviewer Lisa Kennell

DHHS / FDA / CDRH 2 Introduction Regulatory history of BioGlue Clinical Summary Non-clinical testing to be discussed Panel Questions

DHHS / FDA / CDRH 3 FDA Review Team Team LeaderLisa Kennell, B.S. Clinical ReviewerPaul Chandeysson, M.D. Immunology Katherine Merritt, Ph.D. FDA SGEHenry Homburger, M.D. StatisticsT.C. Lu, M.S., M.A. ChemistryEllen Chen, Ph.D. and Srilekha Das, Ph.D.

DHHS / FDA / CDRH 4 Regulatory History IDE initially for adjunct to Type A (ascending) aortic dissection repair, submitted in 1998

DHHS / FDA / CDRH 5 Regulatory History Humanitarian Device Exemption (HDE) submitted June 1999, approved December 1999 for adjunct in repair of Type A and B aortic dissections HDE for treating diseases or patient populations with incidence rate of 4000 or less per year in U.S. no alternatives or alternatives are inadequate FDA reviews only safety and assesses probable benefit Type A and Type B dissections

DHHS / FDA / CDRH 6 Regulatory History After HDE approval, sponsor had protocol deviations in IDE study randomization breaches obtaining patient consent “off label” uses outside of the protocol patient entrance criteria and approved HDE indication began current cardiac/vascular study to address deviations

DHHS / FDA / CDRH 7 BioGlue Indication The indication for use for the BioGlue is “BioGlue Surgical Adhesive is indicated for use as an adjunct to standard methods of cardiac and vascular repair such as sutures (or staples) to provide hemostasis.”

DHHS / FDA / CDRH 8 Clinical Summary

DHHS / FDA / CDRH 9 Clinical Summary BioGlue versus standard hemostasis Superiority Hypothesis 10% improvement in hemostasis with BioGlue 75 patients/treatment group

DHHS / FDA / CDRH 10 Entrance Criteria Include patients needing cardiac or vascular repairs Exclude patients with known hypersensitivity to albumin, bovine products, glutaraldehyde needing intra-cerebral circulation repair needing repair of acute thoracic aortic dissections

DHHS / FDA / CDRH 11 Indication for Surgery Anastomotic Location

DHHS / FDA / CDRH 12 Clinical Summary Primary Endpoint Anastomotic hemostasis (no need for additional agents to control bleeding at any point)

DHHS / FDA / CDRH 13 Clinical Summary Secondary Endpoints Exposure to donor blood products Additional hemostatic agents Re-operation for bleeding Major and Minor adverse events Mortality

DHHS / FDA / CDRH 14 Effectiveness Results Primary Endpoint

DHHS / FDA / CDRH 15 Effectiveness Results Secondary Endpoints

DHHS / FDA / CDRH 16 Effectiveness Results Secondary Endpoints

DHHS / FDA / CDRH 17 Major Safety Results

DHHS / FDA / CDRH 18 Major Safety Results

DHHS / FDA / CDRH 19 Preclinical Data and Discussion Items Immunogenicity

DHHS / FDA / CDRH 20 Summary of Non-Clinical Testing Immunogenicity Buehler hypersensitivity test (no adjuvant) Kligman hypersensitivity test (with adjuvant) Antigenicity in guinea pigs (with ELISA Ag/Ab assay)

DHHS / FDA / CDRH 21 Summary of Non-Clinical Testing Immunogenicity complement activation in vitro Bovine Serum Albumin (BSA) concentration after various polymerization times from 1.5 min to 24 hr via bicinchoninic acid (BCA) and Lowry assays Biodegradation in animals

DHHS / FDA / CDRH 22 Results of Non-Clinical Immunogenicity Testing Ag/Ab ELISA assays resulted in low titers of Ab to BioGlue and to BSA in sensitized groups Lowry assay showed unbound protein, but BCA assay did not Animal studies suggest BioGlue encapsulation or reaction limited to local inflammatory response in most, but some animals showed degradation

DHHS / FDA / CDRH 23 Independent Review Henry Homburger, M.D. Section of Clinical Chemistry and Medical Labs, Mayo Clinic What is the likelihood that a clinical immunologic response will occur? Data presented are not sufficient to reach a firm conclusion Animal studies show that antigen-specific T lymphocytes may persist, but this does not necessarily indicate an increased risk of a clinically significant immunologic reaction

DHHS / FDA / CDRH 24 Independent Review Henry Homburger, M.D. Section of Clinical Chemistry and Medical Labs, Mayo Clinic What is the likelihood that a clinical immunologic response will occur? A transitory immune response is not likely to be clinically significant but may prime the immune system for subsequent exposures, which could be clinically significant Persistence of antigen at the surgical site has a theoretical risk of immune complex mediated disease

DHHS / FDA / CDRH 25 Independent Review Henry Homburger, M.D. Section of Clinical Chemistry and Medical Labs, Mayo Clinic Recommendations: It would be difficult to design further animal studies to evaluate the human risk It is “prudent and advisable” to provide extensive product labeling Caution against the repeated use in the same person Recommend post-market testing for specific antibodies and for in vitro measurement of delayed hypersensitivity

DHHS / FDA / CDRH 26 Panel Questions

DHHS / FDA / CDRH 27 Panel Questions- Effectiveness 1.Please discuss the clinical implications of the primary and secondary endpoint data.

DHHS / FDA / CDRH 28 Panel Questions- Effectiveness 2. The sponsor states in the submission that “Our clinical investigators believe that the routine use of BioGlue in these patients will allow them to modify their blood management protocol and should minimize the potentially life-threatening complication of postoperative hemorrhage.” Please comment on whether there is adequate information to support the statement.

DHHS / FDA / CDRH 29 Panel Questions- Effectiveness 3. Based on the information provided in the premarket approval application, please discuss whether the information supports reasonable assurance of safety and effectiveness of the BioGlue.

DHHS / FDA / CDRH 30 Panel Questions-Labeling 4a. Please discuss the findings of the immunogenicity testing, especially as they relate to BOTH the physician and/or any patient labeling. Should patients be advised of specific adverse events to be aware of that may suggest they are experiencing a sensitization reaction?

DHHS / FDA / CDRH 31 Panel Questions- Immunogenicity 4b.Please discuss the immunogenicity data. Are additional pre- or post- marketing studies needed to assess the immune potential of BioGlue?

DHHS / FDA / CDRH 32 Panel Questions-Labeling 5. Please comment on the INDICATIONS FOR USE section as to whether it identifies the appropriate patient population for treatment with BioGlue? “BioGlue Surgical Adhesive is indicated for use as an adjunct to standard methods of cardiac and vascular repair such as sutures (or staples) to provide hemostasis.”

DHHS / FDA / CDRH 33 Panel Questions-Labeling 6.Please comment on the DIRECTIONS FOR USE as to whether they adequately describe how the BioGlue should be used to maximize benefits and minimize adverse events?

DHHS / FDA / CDRH 34 Panel Questions-Labeling 7.Do you have any other recommendations regarding the labeling of this device?